PROJECT ABSTRACT/SUMMARY Alzheimer's disease (AD) is the most common cause of dementia. Beta-amyloid plaques in the brain on autopsy are one of the key pathological hallmarks of AD, but numerous clinical trials targeting beta-amyloid have failed. Many studies in brain specimens and animal models of AD have shown that iron is found in and adjacent to beta-amyloid plaques and may contribute to neuronal injury. People with evidence of beta-amyloid plaques on positron emission tomography (PET) and high levels of brain iron have accelerated cognitive decline. However, the mechanisms linking iron to cognitive decline in humans remain unclear. Elucidating these mechanisms is critical for the development of potential iron-targeted therapies. The objective of this proposal is to use state-of-the-art magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) markers of iron, oxidative stress, and neuronal injury to understand the link between iron and AD. If successful, this proposal will clarify iron's role as a potential key upstream target in therapeutic trials to slow or stop the development of AD. This application is for a prospective study of 80 elderly normal individuals, half of whom will have PET evidence of cerebral amyloid deposition. The first aim is to test the hypothesis that subjects with cerebral amyloid deposition will have higher baseline levels of brain iron and higher rates of iron accumulation, using quantitative susceptibility mapping, a noninvasive MRI measure of brain iron. The second aim is to test the hypothesis that subjects with cerebral amyloid deposition will have higher baseline levels of oxidative stress and higher rates of increase in oxidative stress, as reflected by lower glutathione levels on proton MR spectroscopy and higher isoprostane levels in the CSF. The third aim is to test the hypothesis that subjects with cerebral amyloid deposition will have greater baseline evidence of AD biomarkers and longitudinal change in AD biomarkers, including CSF markers of beta-amyloid, tau, and hyperphosphorylated tau, brain atrophy and cortical thinning, and memory decline. The results of this proposal will advance our understanding of the role of iron in AD pathogenesis and as a potential therapeutic target for clinical trials.